Shimon ben Shetach lived in the time of the Hasmonean king Alexander Jannaeus. According to the Babylonian Talmud he was the brother of Queen Shlomtzion (Salome Alexandra), although scholars have questioned this reading. He studied under Yehoshua ben Perachya and Nittai of Arbel, and his students included Shemaya and Avtalyon.

Together with Yehudah ben Tabbai he formed the third of the "pairs" (zugot) who transmitted the Oral Torah. Most Talmudic sources call him Nasi of the Sanhedrin, under Alexander Jannaeus and then Queen Shlomtzion, and with his colleague he worked to restore Pharisaic interpretation. Rabbinic literature omits the title "Rabbi" before his name, a sign of his greatness.

Several enactments are credited to him. He ordained that children attend school, whereas instruction had previously been left to fathers. He ruled that the ketubah money would remain in the husband's hands while all his property was pledged to his wife's ketubah, which made hasty divorce harder. He also established that a metal vessel that was melted down and remade retains its impurity.

He was uncompromising in matters of justice. According to the Jerusalem Talmud, eighty witches were executed in Ashkelon in a single day. Afterwards, relatives of those women brought false testimony against his son, who was sentenced to death; the witnesses confessed to their lie as the verdict was being given, yet the sentence was carried out.

Pirkei Avot (1:9) records his teaching: "Be diligent when inquiring of the witnesses, and be careful of your words, lest thereby they learn to lie." He died around 60 BCE, at about eighty years of age.